Childhood asthma exacerbations are frequently associated with respiratory viral infections, more so than in adults[1-3]. Infectious agents such as rhinovirus, Respiratory Syncytial Virus (RSV), human metapneumovirus (hMPV), influenza virus, adenovirus, parainfluenza virus, and coronavirus are frequently identified in respiratory secretions from children with asthma exacerbations[4-9]. Several of these ensure their virulence via various means of immune evasion[10]. For example, RSV and hMPV have been shown to decrease interferon (IFN)-γ expression during acute infection[11-13] which limits the anti-viral cellular immune response. It is tempting to speculate that this type of immune evasion pathway is mechanistically coupled to asthma severity; however, until now, there has been little data to support this.
It is well established that T-helper type (Th2) cytokines predominate in asthma[14-16]. In a previous report, we found a potential molecular connection between respiratory virus-associated IFN-γ reduction and asthma-associated Th2 preponderance[17]. Specifically we found that NKG2A, a key protein receptor for the non-classical MHC class I antigen HLA-E[18-23], is expressed solely on activated Th2, but not Th1, cells[17]. IFN-γ acts at the HLA-E gene promoter to increase HLA-E expression[24]. Thus, we theorized that a viral-induced decrease in IFN-γ expression would result in a relative decrease in HLA-E expression. In turn, lower HLA-E expression would lead to less agonism at Th2 NKG2A receptors. The resultant decrease in NKG2A inhibitory signaling via its immunoreceptor tyrosine-based inhibition motif (ITIM) would lead to relatively increased Th2 cell effector function [25-28].
We previously hypothesized that activation of NKG2A receptors on Th2 cells would be expected to lead to downstream suppression of interleukin (IL)4 expression[17]. Here, we test this hypothesis using purified ex vivo Th2 cells with activation by anti-CD3/CD28 antibodies and challenge with an NKG2A-specific agonist monoclonal antibody, and by describing experiments with a mouse model of viral asthma.